Circulating Biomarkers of Immune Activation Distinguish Viral Suppression from Nonsuppression in HAART-Treated Patients with Advanced HIV-1 Subtype C Infection

Abstract

Few studies have examined immune activation profiles in patients with advanced HIV-1 subtype C infection or assessed their potential to predict responsiveness to HAART. BioPlex, ELISA, and nephelometric procedures were used to measure plasma levels of inflammatory biomarkers in HIV-1 subtype C-infected patients sampled before and after 6 months of successful HAART (n = 20); in patients failing HAART (n = 30); and in uninfected controls (n = 8). Prior to HAART, CXCL9, CXCL10, β2M, sTNF-R1, TGF-β1, IFN-γ, IL-6, TNF, and sCD14 were significantly elevated in HIV-1-infected patients compared to controls (P < 0.01). All of these markers, with the exception of sTNF-R1, were also elevated in patients failing HAART (P < 0.05). The persistently elevated levels of CXCL9, CXCL10, and β2M in patients failing therapy in the setting of a marked reduction in these markers in patients on successful HAART suggest that they may be useful not only to monitor immune activation during HAART, but also to distinguish between good and poor responders. In the case of sCD14 and TGF-β1, the levels of these biomarkers remained persistently elevated despite HAART-induced virological suppression, a finding that is consistent with ongoing monocyte-macrophage activation, underscoring a potential role for adjuvant anti-inflammatory therapy.

Impact of HIV infection and smoking on lung immunity and related disorders

“…Although intended to counter chronic immune activation [40,41], TGF-β1 contributes to HIV-related immunosuppression by several mechanisms, including 1) induction of the transcription factor, Foxp3, a key event in the development of Tregs [39] and 2) promotion of collagen deposition and fibrosis in secondary lymphoid tissues, disrupting T-cell colonisation and function [20]. TGF-β1 has also been implicated in the pathogenesis of various types of cancer, including lung cancer [42,43].…”

“…In addition, TGF-β1, via pro-fibrotic activity, may also contribute to the development of chronic obstructive pulmonary disease (COPD) [44]. It is noteworthy that, even in the setting of HAART-mediated viral suppression, circulating levels of TGF-β1 remain elevated, consistent with ongoing chronic immune activation [41].…”

Immunological Profiles in HIV Positive Patients with or without Opportunistic Infections and the Influence of Highly Active Antiretroviral Therapy: A Systematic Review and Update

“…This may be related to immune restoration following viral suppression. Contrastingly, more recent studies document significant decline of plasma IFN-γ levels with HAART administration among previously untreated HIV-1 infected subjects [31] that may be related to down-regulation of inflammation and immune activation by antiretroviral drug intervention. Collectively, these reported contradictory findings may be attributed to distinct mechanisms of immune activation that are differentially affected by antiretroviral therapy.…”

“…Among the research articles that satisfied the criteria for inclusion, 4 were cross-sectional based in nature [5,21,31,32], 8 were longitudinal studies [27,[33][34][35][36][37][38][39]], 5 were prospective cohort studies [40-44] whereas 2 studies involved use of both cross-sectional and longitudinal study designs [26,45]. Table 1 presents the types of studies, population among other variables included in our review.…”

“…Similarly, antiretroviral treatment has been shown to cause a dysregulation in cytokine expression profiles [26,31]. However, this has not been fully interrogated, more specifically the contribution of each specific antiretroviral agent towards circulating plasma cytokine levels.…”